Alzheimer?s disease (AD) is an immense national public health burden. It is the 6th leading cause of death in the US with over 5.7 million Americans suffering, and costs of over $275 billion in health care and related expenses. This patient population is expected to almost triple over the next 30 years. Despite this urgent need, there are currently no disease-modifying agents approved. Neuron loss is the only physiological phenomena that has been directly linked to the cognition loss in patients, and a major cause of this brain cell death is endoplasmic reticulum (ER) stress-induced apoptosis caused by disrupted intracellular Ca2+ homeostasis. By targeting correction of this altered Ca2+ state, Neurodon has developed a series of novel small molecule positive allosteric modulators (PAMs) of the major ER Ca2+ handling protein, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Our PAMs rescue brain cells in vitro and in vivo, and improve memory and cognition in the APP/PS1 double transgenic mouse model of AD. These results support SERCA activation as a target for the development of disease-modifying therapeutics for AD. The overall goal of Neurodon is the development of effective and orally available drugs to slow or halt AD progression. In this initial Phase 1 proposal we will partner with the chemistry expertise and facilities at Northwestern University to deliver advanced leads having potential for oral availability and improved efficacy. These goals will be accomplished by pursuing the following Aims: 1) Perform hit-to-lead and lead optimization on our novel series of SERCA2b PAMs to improve biological activity and physical properties. Using synthetic chemistry, structure-based drug design, and ADME profiling, we will optimize our novel series to improve efficacy and enable oral administration. 2) To characterize our synthesized SERCA PAMs in cellular and functional assays to assess their efficacy and prioritize development candidates. We have developed 2 complimentary assays to rapidly vet our newly synthesized leads for potential as drug development candidates. Ultimately, the results of these proposed Aims will be the delivery of drug molecules to be advanced to candidate-seeking development activities including efficacy and toxicological studies in Phase 2.